Inflammatory monocytes promote progression of Duchenne muscular dystrophy and can be therapeutically targeted via CCR2

Abstract

Myofiber necrosis and fibrosis are hallmarks of Duchenne muscular dystrophy (DMD), leading to lethal weakness of the diaphragm. Macrophages (MPs) are required for successful muscle regeneration, but the role of inflammatory monocyte (MO)-derived MPs in either promoting or mitigating DMD is unclear. We show that DMD (mdx) mouse diaphragms exhibit greatly increased expression of CCR2 and its chemokine ligands, along with inflammatory (Ly6Chigh) MO recruitment and accumulation of CD11bhigh MO-derived MPs. Loss-of-function of CCR2 preferentially reduced this CD11bhigh MP population by impeding the release of Ly6Chigh MOs from the bone marrow but not the splenic reservoir. CCR2 deficiency also helped restore the MP polarization balance by preventing excessive skewing of MPs toward a proinflammatory phenotype. These effects were linked to amelioration of histopathological features and increased muscle strength in the diaphragm. Chronic inhibition of CCR2 signaling by mutated CCL2 secreted from implanted mesenchymal stem cells resulted in similar improvements. These data uncover a previously unrecognized role of inflammatory MOs in DMD pathogenesis and indicate that CCR2 inhibition could offer a novel strategy for DMD management.

A Porcine Urinary Bladder Matrix Does Not Recapitulate the Spatiotemporal Macrophage Response of Muscle Regeneration after Volumetric Muscle Loss Injury

“…A prolonged inflammatory response disrupting tissue healing is not new and has been well documented in muscle disorders like muscular dystrophy. The repetitive cycles of degeneration-regeneration of myofibers as seen in muscular dystrophy causes the sequential invasion of M1 and M2 macrophages, respectively, resulting in fibrosis of the muscle [Madaro and Bouche, 2014;Mojumdar et al, 2014;Munoz-Canoves and Serrano, 2015]. Similarly, herein, the remodeling of the scaffold into a fibrotic scar-like tissue can in part be attributed to the heightened and protracted M1 response.…”

Quantitative Analysis of Immune Cell Subset Infiltration of Supraspinatus Muscle After Severe Rotator Cuff Injury

“…COX-2 lo MΦ, which are phenotypically similar to CD206 + MΦ, protect myotubes against atrophy in vitro [47]. In contrast, classical Ly6C hi MO promote chronic muscle degeneration in mdx mice[48]. Taken together, these findings suggest that non-classical MO and MΦ may support SS integrity compared to their classical counterparts that may feed forward degeneration.…”

“…MO and MΦ counts are 2.3×10 4 and 3.0×10 4 cells/g at day 7 following TT+DN (Fig 1). In degenerative muscles of the mdx mouse model of muscular dystrophy, MΦ counts vary from 6×10 4 to 3×10 6 cells/g at 6–12 weeks of age[48], [51]. After toxin-induced skeletal muscle injury, MO/MΦ infiltration is dramatically higher, reaching a maximum of 1.4×10 7 cells/g at day 7[52].…”

Regulatory T Cells Promote Myositis and Muscle Damage in Toxoplasma gondii Infection

“…Recent studies implicate a tissue-specific role for resident regulatory T-cells (Tregs) in the transition from IM/M1 to M2 during tissue repair in acute sterile injury and dystrophy models (12, 13). Still, greater insight into how repair proceeds in the face of immune dysfunction and chronic inflammation is needed as these are hallmark features of a variety of debilitating inflammatory myopathies such as polymyositis, dermatomyositis, and idiopathic inflammatory myositis (6, 14–16). …”